This study targets atherosclerosis, a chronic inflammatory disorder of the blood vessel wall, which underlies nearly 50% of all deaths in westernized countries and is the primary cause of mortality in patients with diabetes. This proposal utilizes rational molecular design approaches to a novel class of therapeutics - amphiphilic polymers that serve as athero-protective and anti-inflammatory therapeutics. The most innovative component is that molecularly designed polymers may have the potential to inhibit atherosclerosis by multiple scavenger receptor targeting and blockage during the early stages of atherogenesis. This binding behavior could be critical to blocking oxidized LDL uptake and more effectively abrogate the athero-inflammatory cascade, and retard the progression of atherosclerosis. The central hypothesis regarding the enhanced polymer structures is that combinations of strengthened hydrophobic features in conjunction with anionic charge and hydrophilic tails will yield polymers with optimal targeting to multiple scavenger receptors on both macrophages and endothelial cells, specifically SR-A, CD36 and LOX-1. To test this hypothesis, three specific aims are proposed. Aim 1 is focused on the molecular modeling (docking and scoring) and design of novel polymer classes for enhanced binding to multiple scavenger receptors. This effort will yield new polymer structures with a more rigid and space-filling backbone that, in conjunction with charge and hydrophilicity, enhance binding affinities to scavenger receptors - particularly under physiologic conditions. Aim 2 is focused on investigating the molecular mechanisms and polymer interactions with cultured macrophages and endothelial cells for inhibition of athero-inflammation in vitro. Aim 3 is focused on the evaluation of in vivo polymer efficacy in terms of binding to atherosclerotic lesions and degree of regression of athero-inflammatory markers using an animal model of accelerated atherosclerosis. At minimum, new insights will be obtained regarding multiple scavenger receptor blocking as a strategy to counteract the progression of atherosclerosis. The potential impact of this research proposal is high; the overall outcome may be a new approach to treating coronary artery disease - using enhanced polymers as multifunctional inhibitors.